D-homo steroids containing a -cho group in 18-position



United States Patent 3,345,385 D-HOMO STEROIDS CONTAINING A CHO GROUP IN18-POSITION Wataru Nagata, Hyogo Prefecture, Japan, assignor to Shionogi& Co., Ltd., Osaka, Japan No Drawing. Original application July 27,1961, Ser. No. 127,097, now Patent No. 3,206,472, dated Sept. 14, 1965.Divided and this application -May 12, 1965, Ser. No. 464,264 7 Claimspriority, application Japan, Apr. 4, 1960, 35/20,].25; Apr. 6, 1960,35/20,723 2 Claims. (Cl. 260-3403) The present application is a divisionof copending patent application, Ser. No. 127,097, filed July 27, 1961(now US. Pat. No. 3,206,472). Application Ser. No. 127,097 is acontinuation-in-part of copending applications Ser. Nos. 93,869, 94,988,98,334 and 103,741 filed respectively on Mar. 7, 1961, Mar. 13, 1961,Mar. 27, 1961, and Apr. 14, 1961 (all now abandoned).

This invention relates to compositions of matter, particularly organiccompounds and their methods of preparation, and more especially tointermediates useful in the total synthesis of steroids and to thepreparation of such intermediates. More particularly, the presentinvention is concerned with the provision of novel intermediates of theformula CHO wherein R represents and the ripple mark (2) is a genericindication of both the aand B-configurations, and intermediates thereof.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

In the examples which follow, the abbreviations and symbols have thefollowing significances:

g. means grams(s),

1. means liter(s), m means milliliter(s), kg. means kilograms(s), mg.means milligram(s), hr. means hour(s), m. means molar, Anal. Calcd.means analysis calculated, and MP. means melting point. Otherabbreviations and symbols have conventional significances.

EXAMPLE 1 OHsOOO 00011 coo O IA...()H

2 HO 5 H0 A solution of mg. of d1-3fi-acetoxy-13,8-cyano-D- .7

homo-5a-androstan-17-one ethylene ketal, which is obtained by ketalationof dl-3,B-acetoxy-13,8-cyano-D-homo- 5u-androstan-17-one with ethyleneglycol, in 8 ml. of tetrahydrofuran is stirred dropwise with externalice-cooling and in the course of Sminutes into a solution of lithiumaluminum diethoxyhydride in tetrahydrofuran, prepared from 15.5 ml. of.0.3 12 M-1ithium aluminum hydride solution in tetrahydrofuran and 350mg. of ethyl acetate. The mixture is stirred for 30 minutes undericecooling and then 3.5 hours at room temperature, cooled, and 4 ml. of0.886 M-sodium potassium tartrate solution and 0.36 ml. of 0.5M-tartaric acid solution added. The reaction mixture is extracted 3times with chloroform. The combined extract is washed with Water, dried,and distilled under reduced pressure to give 214 mg. of residue. Thiscorresponds to a mixture of an iminomethyl compound and a smallquantityof an aldehyde and the starting cyano compound, as interpretedby IR determination, thus shows absorption at 3508 and 3458corresponding to OH, 3258 and 1635 corresponding to CH=NH group, 2218corresponding to CN, and 2700 and 1716 cm.- corresponding to CH group.The residue is dissolved in 9 ml. of methanol, and after addition of 1ml. of 2 N-sodium hydroxide, refluxed for minutes. After neutralizationwith acetic acid, the reaction mixture is extracted 3 times withchloroform. The combined extract is washed With water, dried, solventdistilled off under reduced pressure, and is subjected to acetylationwith 3 ml. of acetic anhydride and 5 ml. of anhydrous pyridine at roomtemperature for 1 night. The crude product, 224 mg., is chromatographedon alumina (Wehn HI, neutral). From the fraction of petroleumether-benzene (4:1-7z3) 34.8 mg. ofdl-3fl-acetoxy-17-oxo-D-homo-Son-androstan-18-al 17- ethylene ketal,M.P. 172179 C. (with foaming), is obtained after recrystallization fromacetone-ether.

IR: 1121322742 (CHO), 2680 (CHO), 1726 (011 000, CHO), 1708 (CHO); 1122,1099 (ethylene ketal); 1247, 1022 (CH COO) cur- Anal. Calcd. for C H O(404.53): C, 71.25; H, 8.91. Found: c, 71.00; H, 8.92.

The second fraction of petroleum ether-benzene (312-327) gives 62 mg. ofthe starting material, M.P. 230-237" C., after recrystallization fromacetone-ether.

Eighty mg. of dl-3,8-acetoxy-17-oxo-D-homo-5a-androstan-lS-al17-ethylene ketal are dissolved in 15 ml. of acetone, freshly distilledafter treatment with potassium permanganate, and added dropwise with 0.5ml. of 8 N chromic-sulfuric acid mixture (J. Chem. Soc., 1953, 2548)with stirring. The further stirring is continued for 20 minutes. Then,the reaction mixture has added there-to 5 drops of methanol and 5 0 ml.of water and is extracted 3 times with chloroform. The extracts arecombined, washed with water, and dried over sodium sulfate. Afterremoving the solvent, the residue (119 mg.) is dissolved in 1.0 ml. ofacetone, 2 N hydrochloric acid (2 ml.) added and the mixture boiled for30 minutes. After the addition of anhydrous sodium acetate (300 mg.),the mixture (124.3 mg.) is dissolved in 1 ml. of N-sodium carbonate and10 ml. of methanol and boiled for 1.5 hrs. After removing methanol bydistillation, water is added to the residual solution, which isextracted 3 times with chloroform. The chloroform solution is extractedtwice with 2 N sodium hydroxide. The combined alkaline extracts areadjusted to pH 3 by the addition of concentrated hydrochloric acid undercooling, and extracted with chloroform. The extracts are washed withwater, dried and distilled to give 37 mg. of crude crystals ofdl-3fl-hydroxyl7-oxo-D-l1omo-5u-androstan-1-8-oic acid. Thisequilibrates with the hemiketal lactone form. This forms leafletcrystals of M.P. 310 C. (with decomposition) by recrystallization fromchloroform-acetone.

IR: 7 3540, 3265 (OH); 1733 (hemiketallactone),

max. 1710 (OOOH, CO) cm.-

Anal. Calcd. for C H O (334.44): C, 71.82; H, 9.04. Found: C, 71.82; H,9.14.

Thus obtained dl-3B-hydroxy-l7voxosD-homo-5a-androstan-lS-oic acid (37mg.) is esterified by ethereal solution of diazomethane in dioxane andtreated as usual to obtain crude methyl ester (36.8 mg). Furtherrecrystallization from acetone-ether gives pure prismatic crystals 4 ofmethyl dl-3,8-hydroxy-17-oxo-D-homo-5a-androstan- 18 oate, M.P. 193194C.

EXAMPLE 2 CHsCOO OH ...OH.

CHaCOO- e A solution of 138.5 mg. of dl-3fi-acetoxy-13B-cyano-D-h0rn0-5oc-3I1dr0stan-17-One ethylene ketal in 10 ml. oftetrahydrofuran is added to 20 ml. of 0.172 M-lithium aluminum hydridesolution in tetrahydrofuran under icecooling and stirring in the courseof 30 minutes and the stirring is continued at room temperature for 3more hours. The reaction mixture is cooled, 10 ml. of water added, andthen refluxed for 8 minutes to hydrolyze the imino compound. Afterconcentration to a half volume under reduced pressure, the reactionmixture is neutralized by acetic acid and extracted 3 times withchloroform. The chloroform solution is washed with water, dried anddistilled to remove the solvent. To the residue (142.4 Y

hOIllO-Soc-QlldIOStEin-lS-fll 17-ethylene ketal are obtained ascrystals, M.P. -l79 C., after recrystallization with acetone-ether. Byfurther recrystallization, the mother liquor gives 20.4 mg. more of thecrystals.

Thus obtained dl-3 3-acetoxy-17-oxo-D-homo-5a-androstan-18-aldehyde17-ethylene ketal (60 mg.) is admixed with potassium hydroxide (106 mg),80% hydrazine hydrate (0.3 ml.) and triethyleneglycol (2 ml.) and heatedat 130-135 C. for 1 hr. The reaction temperature is gradually elevated.During the elevation, excess of hydrazine hydrate and water aredistilled off. Then, the mixture is heated at 210-220 C. for 3 hrs.After cooling, the mixture is poured into ice-Water and extracted withchloroform. The extract is washed with water, dried and evaporated todryness. The residue (65.9 mg.) is recrystallized from ethanol to givedl-3B-hydroxy- D-homo-5a-androstan-17-one ethylene ketal (34.8 mg), asplates, M.P. 221223 C.

IR (Nujol): 3602, 3551, 1102, 1075 cm.-

Anal. Calcd. for C H (348.51): C, 75.81; H, 10.41. Found: C, 75.71; H,10.38.

Acetylation of dl-3fi-hydroxy-D-homo-5a-androstan-17- one ethyleneketalgives dl-3p-acetoxy-D-homo-5a-androstan-17-one ethyleneketal, M.P.164-166/ 173174 C.

IR (Nujol): 1731, 1241, 1028, 1020, 1102, 1078 cm.

Anal. Calcd. for C H 'O (390.54): C, 73.80; H, 9.81. Found: C, 73.76; H,9.80.

Deketalization of dl-3,B-acetoxy-D-homo-5a-androstan- 17-oneethyleneketal gives dl-3B-acetoxy-D-homo-5a-androstan-17-one, M.P.160163 C.

IR (Nujol): 1739, 1711, 1248, 1239, 1928 cmf Anal. Calcd. for C H O(346.49): C, 76.26; H, 9.89. Found: C, 76.30; H, 9.77.

To an ether solution of Grignard reagent which is prepared from methyliodide (2.07 g.) and magnesium (356 mg.) in anhydrous ether (14 ml.) isadded dropwise another solution ofd1-3fi-acetoxy-D-homo-5u-androstan-l7- one (513.7 mg.) in anhydrousbenzene (15 ml.) with stirring under ice-cooling. The dropwise additiontakes 20 mins. The mixture is stirred for 1 hr. at room temperature andether is distilled off. After addition of anhydrous benzene (30 ml.),the mixture is refluxed for 2.5 hrs. Then the mixture is ice-cooled,N-hydrochloric acid (20 ml.) is added and the mixture is extracted 5times with chloroform-methanol (3:1). The extract is washed twice with ahalf-saturated aqueous solution of sodium sulfate, dried over anhydroussodium sulfate, and evaporated. To the residue (623.9 mg.) are addedacetic anhydride (4 ml.) and dry pyridine (5 ml.) and allowed to standovernight at room temperature. Thus obtained crude acetate (671.6 mg.)is recrystallized from acetone-ether to give 17a methyl D homo androstan318,17/3 diol 318- acetate (291.1 mg.) as prisms, M.P. 142-144/162-163"C. (it melts once at 142144 C., then solidifies and melts again at162-163 G). Then, 151.2 mg. more of the product are obtained from themother liquor. Totally, 442.3 mg. of17a-methyl-D-hOmo-Sa-androstan-3fi,1719- diol S-acetate are obtained.

The configuration of the methyl radical in the 17-position is confirmedsynthetically.

EXAMPLE 3 CHaCO O CHO wherein R is a radical selected from the groupconsisting of oxo and ethylenedioxy when R is divalent, and from thegroup consisting of hydroxy and acetoxy when R is monovalent, R"" is aradical selected from the group consisting of oxo and ethylenedioxy, andthe ripple mark (5) is a generic indication of the aandB-configurations.

2. 3,6 acetoxy 17 oxo D homo 5a androstan- 18-al 17-ethylene ketal.

(References on following page) 7 I 8 References Cited 2,946,805 7/ 1960Kleinschmidt 260-3265 3,153,087 10/1964 Kramer et a1 260515 UNITEDSTATES PATENTS salzberg et 260243 ALEX MAZEL, Primary Examiner. Calva16722 5 Abbott et aL 26O, 340'9 NICHOLAS RIZZO, Exammer.

Mikeska 260-465 J TOVAR, J. TURNIPSEED, Assistant Examiners.

1. A COMPOUND OF THE FORMULA: